DESCRIPTION: (Verbatim from the applicant's abstract) Severe respiratory failure affects approximately 150,000 patients a year in the United States, and is still associated with a 40 degrees about mortality despite recent advances in critical care. Unfortunately, mechanical ventilation targeted to restore normal blood gases causes high peak airway pressure with iatrogenic barotrauma or volutrauma to relatively compliant normal lung tissue, exacerbating lung injury. Therefore, "kind, gentle ventilation" in which peak inspiratory pressures (PIP) and fraction of inspired oxygen are minimized, accepts the obligate increase in arterial pCO2 levels, termed "permissive hypercapnia." Adverse effects of permissive hypercapnia and the associated respiratory acidosis include increased cardiac output, organ blood flow and intracranial pressure. Arteriovenous carbon dioxide removal (AVCO2R) utilizing a low-resistance gas exchanger in a simple percutaneous arteriovenous shunt achieves near-total extracorporeal removal of CO2 production with only 800-1200 mL/min flow. From our animal and initial patient safety trials, AVCO2R allows decreased respiratory rate, tidal volume, and peak airway pressures such that PIP is predictably less than 30 cm H20 and respiratory rate 4 about breaths/minute with no significant decrease in WBC, platelets, plasma Hgb, or increased complement levels. AVCO2R, therefore, is capable of providing near-total extracorporeal removal of carbon dioxide production during acute respiratory failure, while rnaintaining CO2 and pH homeostasis. We will test the hypothesis that severe respiratory failure is best treated with AVCO2R for respiratory support to promote lung recovery. Specifically, we will conduct a prospective, randomized, controlled, unblinded, multicenter outcomes study to compare percutaneous arteriovenous extracorporeal carbon dioxide removal (AVCO2R) in acute hypercapnic respiratory failure to standardized "gentle" ventilation on all cause mortality and ventilator free days in patients with ARDS who require standardized pressure controlled mechanical ventilation (SMV) with perrnissive hypercapnia. The secondary objectives are: characterization of the safety of AVCO2R versus SMV and assessment of the effects of AVCO2R relative to SMV on oxygenation, pulmonary mechanics, ventilator settings, acute blood/surface mteractions (platelet count, complement C3a, Csa, TNFa, IL-1b, IL , IL-10), and long-term morbidity including safety (overall mortality, adverse events, neuropsychologic testing), oxygenation (oxygenation index), PaO2, FiO2, CO2 removal (PaCO2), total duration of mechanical ventilation (time to unassisted ventilation), proportion of patients alive and off the ventilator, multiple organ dysfunction score, ALI/ARDS "time to resolution," chronic lung disease, and psychological assessment. The principle end-points of AVCO2R assessment include: changes in PaCO2 and pH, decreases in level of mechanical ventilatory support, and changes m PaCO2 and pH associated with "trials-off'. The knowledge gained will establish the gas exchange capabilities of low-pressure (gentle) mechanical ventilation with pH-controlled permissive hypercapoia compared to percutaneous AVCO2R to improve outcomes in patients with severe respiratory failure from ARDS.